chr12-105223192-G-A

Position:

• chr12-105223192-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000258530.8(APPL2):​c.154-5467C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 152,012 control chromosomes in the GnomAD database, including 11,574 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.38 (11574 hom., cov: 32)
• Consequence: APPL2 ENST00000258530.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.739

Genes affected

APPL2 (HGNC:18242): (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 2) The protein encoded by this gene is one of two effectors of the small GTPase RAB5A/Rab5, which are involved in a signal transduction pathway. Both effectors contain an N-terminal Bin/Amphiphysin/Rvs (BAR) domain, a central pleckstrin homology (PH) domain, and a C-terminal phosphotyrosine binding (PTB) domain, and they bind the Rab5 through the BAR domain. They are associated with endosomal membranes and can be translocated to the nucleus in response to the EGF stimulus. They interact with the NuRD/MeCP1 complex (nucleosome remodeling and deacetylase /methyl-CpG-binding protein 1 complex) and are required for efficient cell proliferation. A chromosomal aberration t(12;22)(q24.1;q13.3) involving this gene and the PSAP2 gene results in 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APPL2	NM_018171.5	c.154-5467C>T		intron_variant		ENST00000258530.8	NP_060641.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APPL2	ENST00000258530.8	c.154-5467C>T		intron_variant		1	NM_018171.5	ENSP00000258530	P1

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57260 AN: 151894 Hom.: 11584 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.420

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.436

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.542

Gnomad NFE AF: 0.431

Gnomad OTH AF: 0.424

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.377 AC: 57256 AN: 152012 Hom.: 11574 Cov.: 32 AF XY: 0.380 AC XY: 28263 AN XY: 74308

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.420

Gnomad4 ASJ AF: 0.566

Gnomad4 EAS AF: 0.436

Gnomad4 SAS AF: 0.480

Gnomad4 FIN AF: 0.432

Gnomad4 NFE AF: 0.431

Gnomad4 OTH AF: 0.419

Alfa AF: 0.432 Hom.: 13744

Bravo AF: 0.366

Asia WGS AF: 0.374 AC: 1303 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1196768; hg19: chr12-105616970;